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Respiratory Management (Rehab Phase)

Phrenic Nerve and Diaphragmatic Stimulation

Electrical stimulation options for the restoration of inspiratory muscle function in subjects with spinal cord injuries include bilateral phrenic nerve pacing, bilateral diaphragmatic pacing and combined intercostal muscle stimulation with unilateral phrenic pacing (DiMarco et al. 2005b).

Intact phrenic nerves are required for successful stimulation. Phrenic nerve function is generally assessed through phrenic nerve conduction studies and fluoroscopic observation of diaphragmatic movement with phrenic nerve stimulation. Subjects with injuries at C3, C4 and C5 may have compromised diaphragmatic function, but are unlikely to be candidates for pacing due to inadequate phrenic nerve function.

Bilateral phrenic nerve stimulation was first reported by Glenn and colleagues in the 1970s. The original surgery involved a thoracotomy and inpatient hospital stay to place the electrodes on the phrenic nerves in the neck or thorax. Potential risks included direct injury to the phrenic nerves during surgery. The original protocols applied intermittent high frequency stimulation to the diaphragms in an alternating pattern, but were revised to a continuous lower frequency stimulation to decrease diaphragmatic fatigue (Glenn et al. 1984; Elefteriades et al. 2002).

In recent years, the laparoscopic placement of intramuscular diaphragmatic electrodes has eliminated the need for more extensive thoracotomy surgery and associated hospital stays. The approach has also decreased the risk of phrenic nerve injury (DiMarco et al. 2005a). The electrodes are placed laparoscopically as a day surgery procedure with optimum placement of the electrodes being mapped to the phrenic nerve motor point (Onders et al. 2004).

Most patients with diaphragmatic pacemakers continue to have tracheostomies and mechanical ventilators as a back-up to their pacemakers. It is important to note that diaphragmatic pacemakers only improve inspiratory function and do not target expiratory functions such as coughing and clearing secretions. Given the small number of controlled trials and large number of pre-post trials, the full data extraction and scoring are only shown for the controlled trials with a briefer summary of the level 4 evidence.

Author Year; Country Score Research Design Total Sample Size

Methods Outcome

Hirschfeld et al. 2008; Germany Cohort
N = 37

Population: 64 SCI participants who were primarily mechanically ventilated through tracheostomy; 32 were treated with PNS and 32 were treated with MV over 20 years.
Treatment: MV or PNS.
Outcome Measures: Incidence of RI.
  1. Incidence of respiratory infection (RI) was equal during 120 days prior to use of final device (1.43 in PNS group and 1.33 in MV group) whereas after PNS, the incidence of RI was 0 compared to 0.14 for MV group.
  2. Two versus 0 returned to work and 9 versus 2 returned to school on PNS compared to MV group, respectively.

Esclarin et al. 1994; Spain
Case Control N=22

Population: 22 participants with either: diaphragmatic pacemaker (DP) (n=9) or mechanical ventilator (MV) (n=13); mean (SD) age: 10.6(2.5) years (DP group) and 35(5.5) years (MV group); Injury level: C1 (n=10), C2 (n=9) or C3 (n=3).
Treatment: Diaphragmatic pacemaker or mechanical ventilation. Retrospective study with follow up information from last clinical examination or by a telephone call.
Outcome measures: Respiratory complications (atelectasis and pneumonia); functional status (ability to remain seated at 50-90o, skill to drive electric wheelchair, use of phonetic language); satisfaction with treatment; cost of maintenance materials; cause of death.
  1. Respiratory problems: DP group produced less bronchial secretions; type of organisms found similar for both groups.
  2. No significant differences between groups with respect to functional status.
  3. Satisfaction with treatment significantly better for the DP group.
  4. Mean yearly cost of materials higher for MV group.
  5. Deaths: 4 deaths in DP group: pneumonia (n=2), cardiogenic shock (n=1), unknown (n=1). 1 death in MV group, presumably due to inappropriate home care.

Carter 1993; USA Case Control N=42

Population: 42 participants: PNS (13M 10F) and MV dependent group MV (17M 2F). Age: (PNS group only) 4-54 years.
Treatment: Retrospective review of PNS implants and 24 hour/day MV.
Outcome measures: Survival status.
  1. PNS group: average time from onset to implantation was 14.4 (still alive) and 14.8 (died) months; average time from surgical implant to death was 47.7 months.
  2. Mechanical ventilation group: survived an average of 96 months.
  3. 61% survival status with PNS and 37% with MV.

Carter et al. 1987; USA Case Control N=37 (some of same participants as Carter 1993)

Population: 37 participants: PNS (9M 9F) and MV (17M 2F).
Treatment: Retrospective review of PNS implants and 24 hour/day MV.
Outcome measures: Survival status.
  1. PNS group: 6/18 (32%) had died; MV: 7/19 (39%) had died.
  2. Onset of injury to death in MV was 3 times earlier than that of PNS group.
Author Participants Intervention Outcomes Complications
DiMarco et al. 2014
Netherlands
Pre-Post
N = 10
10 individuals with complete SCI (8M, 2F). Users of spinal cord stimulation device for >= 2 years Mean (SD) age: 35.6 (13.4) years Median (SD) DOI: 8.7 (3.5) years. Implanted spinal cord stimulation device.
  1. 1. Significantly greater maximum expiratory pressure (MEP) during SCS at 1 year and 4.6 (mean) year follow- up, compared to pre-implant.
  2. Significantly lower frequency of suctioning / assisted cough (S/AC) and severity of S/AC episodes at 1 year and 4.6 (mean) year follow-up, compared to pre-implant.
  3. Significantly less difficulty and greater ease in raising sputum at 1 year and 4.6 (mean) year follow-up, compared to pre-implant.
1. Seven of the 10 participants continue to experience mild leg jerks with stimulation, but these are painless and do not interfere with use of the device.
Kaufman et al. 2015

N=14 ventilated SCI patients with phrenic nerve lesions; 11M, 3F; Median (range) age: 27 (10-66).

Diaphragmatic pacemaker implantation and bilateral nerve transfer.

13 patients showed diaphragm reinnervation; 8 patients achieved >1 h/day ventilator weaning; 2 patients recovered voluntary diaphragm control and spontaneous respiration without pacemaker.

No intraoperative complications; 1 patient developed bilateral pleural effusions; 3 patients required revision surgery for replacement ore repositioning of receiver.
After final data collection, 1 patient expired due to cardiac arrest, 1 patient stopped pacing.

Posluszny et al. 2013

N=29 (27M, 2F); of which N=7 were non- stimulatable (7M); mean (range) age: 31.4 (17-65).

Diaphragm pacer implantation.

16/22 completely weaned within a mean of 10.2 days, 18/22 within 180 days.
3/22 partially weaned. (mixture of mech. ventilation and pacer)
8/22 complete recovery of respiration and pacer removal.

1 patient successfully implanted but had life-prolonging measures withdrawn.

Hirschfeld et al. 2013

N=35 (26M, 9F);
age at implantation 28 (19) 2–71 yrs.

Phrenic nerve stimulation.

27 patients (77%) had stable threshold current over an average of 6.3yrs.

Eight of 35 had threshold currents that exceeded 1mA, which might be suggestive of surgical trauma, infection, or reaction to foreign body.

Tedde et al. 2012

N=5 (3F, 2M), participants with C-SCI; ages 16-40yrs; Level: C2C3 to C4C5.

Implantation of a laparoscopic diaphragmatic pacing stimulation (DPS).

The diaphragmatic pacemaker placement was successful in all of the patients. After 6 mos, 3 used DPS for 24 hrs, 1 used DPS for up to 6 hrs complemented by mechanical ventilation and 1 discontinued DPS.

Two patients presented with capnothorax during the perioperative period, which resolved without consequences.
Diaphragmatic stimulation was discontinued in one patient after onset of uncontrolled neuropathic pain.

Alshekhlee et al. 2008

N = 26, chronic tetraplegia C1- C4 (25 traumatic, 1 non-traumatic).

Diaphragm pacing system.

25/26 were able to pace off the ventilator for more than 4 hours per day.

One patient experienced severe muscle cramping and could not achieve conditioning.

DiMarco et al. 2005a

N = 5, ventilator -dependent tetraplegia.

Laparoscopic placement of intramuscular diaphragm electrodes.

4/5 achieved substantial inspired volumes and were maintained without mechanical ventilatory support for prolonged time periods.
1/5 had no response to stimulation.

1/5 developed pneumothorax.
1/4 developed shoulder pain during maximum stimulation, and another had intermittent aspiration of food during meals.

DiMarco et al. 2005b

N = 4, ventilator -dependent tetraplegia with unilateral phrenic nerve function.

Inspiratory intercostal muscle stimulation combined with phrenic nerve (thoracic) stimulation.

4/4 achieved inspired volumes such that they could be maintained off mechanical ventilation between 16 and 24 hours a day.

Stimulation of the upper thoracic region was associated with mild flexion of the hand and upper trunk musculature. 1/4 participants developed symptoms of autonomic dysreflexia with stimulation, 1/4 developed shoulder pain, while another developed an infection at the receiver site.

Onders et al. 2004

N = 28 (mapping group) N = 6 tetraplegia implantation group).

Mapping the phrenic nerve motor point via electrical stimulation, and laparaoscopic diaphragm pacing

The phrenic nerve motor point was found in 23/28 participants.
5/6 had successful implantation, with three completely free of the ventilator and 2 progressively increasing their time off the ventilator.

One patient had asymptomatic small pneumothorax, and another had a wound infection.

Elefteriades et al. 2002

N = 12, C1/2 – C2 tetraplegia

Bilateral phrenic nerve stimulation and diaphragm conditioning.

Long-term follow up outcomes.
6/12 paced full- time (mean 14.8 years)
1/12 paced full-time for 6.5 years before lapsing to part time
3/12 paced for an average of 1.8 years before stopping
2/12 were deceased: 1 paced for 10 years.

Patients who stopped pacing full- time did so due to inadequate financial or social support, or because they were institutionalized.

Krieger et al. 2000

N = 6, C3-C5 tetraplegia.

Intercostal to phrenic nerve transfer; phrenic nerve stimulation.

5/6 cases have had longer than 3 months for axonal regeneration.
5/5 regained diaphragmatic motion with phrenic stimulation.

None reported.

Mayr et al. 1993

N = 15, C0 – C2/3 tetraplegia.

Phrenic nerve (thoracic) stimulation via a fully implantable device.

11/15 achieved chronic pacing (auxiliary breathing range 1 – 3 hours)
1/15 still depends on mechanical ventilation
3/15 were in post-operative conditioning.

Broken electrodes.
Baer et al. 1990

N = 9 with 7 SCI C2- tetraplegia.

Bipolar and four-pole phrenic nerve stimulation.

5/7 SCI no longer required a mechanical ventilator.
3/7 died (felt to be unrelated to stimulators).

Reoperations were common (7/9) due to technical failure and receiver/implant dislocations.

Miller et al. 1990

N = 23, C1 – C5 tetraplegia.

Phrenic nerve (neck and thorax) stimulation.

8/23 achieved full time pacing.
9/23 required mechanical ventilation at night.
3/23 moderately improved condition.
3/23 showed no response.

3/23 diaphragm failed to pace at time of surgical exploration
3/23 developed pneumonia but cleared in all of them.
There were three instances of equipment failure.

Nakajima & Sharkey 1990

N = 15, C1-C3, brainstem tetraplegia

Phrenic nerve (14 – neck, 1 – thorax) stimulation.

11/15 achieved full time pacing
2/15 achieved half-time pacing
2/15 showed no response

Of the two that failed to experience benefits: one developed perineural fibrosis around the phrenic nerve thereby inhibiting stimulation, and the other (a four year old child) showed loss of nerve viability.

Sharkey et al. 1989

N = 15, high cervical tetraplegia.

Phrenic nerve (14/15 neck and 1/15 thoracic) stimulation.

13/15 achieved full time pacing (including 1 who at the time of follow up did so for 16 years).
2/15 achieved half-time pacing.

Equipment failures, in one case, fibrosis around the electrode resulted in failure to stimulate the nerve, in another case, infection required the removal of the system.

Glenn et al. 1984

N = 5, 4 high cervical tetraplegia, 1 cord infarction.

Phrenic nerve (thoracic) stimulation; uninterrupted simultaneous pacing of both hemidiaphragm s, using low frequency stimulation.

5/5 achieved full time pacing

In one 7-year old patient, ventilatory requirements were not always fully met through continuous pacing, as evidenced by mild hypercapnia and hypoxemia.

Oakes et al. 1980

N = 11, 10 high cervical tetraplegia.

Phrenic nerve stimulation.

3/11 achieved full time pacing 6/11 achieved part time pacing
2/11 had no benefit

Malfunctioning and nonfunctioning devices, pain, pneumothorax.

Glenn et al. 1976

N = 37, C1-C5 tetraplegia.

Phrenic nerve stimulation

13/37 paced full-time
10/37 paced half-time
14/37 could not be paced ≥50% of the time.

Injuries to the phrenic nerves, malfunctioning pacemakers, infection, pain in neck due to stimulation, pain in chest and abdomen.

Discussion

Recent studies show higher success rates with long-term implantation (DiMarco et al. 2014; Hirschfeld et al. 2013); 77% of patients had stable threshold currents for an average of 6.3 yr. An earlier report by the same first author (Hirschfeld et al. 2008) prospectively compared subjects receiving phrenic nerve stimulation and those receiving mechanical ventilation. Although they show decreased rates of respiratory infections and increased social participation in the phrenic nerve stimulation group, they acknowledge that the mechanical ventilation group is not a comparable group as these subjects were not usually candidates for phrenic nerve stimulation.

A retrospective case control study suggests a higher survival rate in a phrenic nerve paced group compared to a mechanically ventilated group (Carter 1993). The prospective study by Hirschfeld et al. (2008) shows no difference in duration of life between the phrenic nerve paced group and mechanically ventilated group.

Hirschfeld et al. (2008) comment on decreased costs of care, improved quality of speech and higher rates of social participation in the phrenic nerve group. The increased rates of return to work and school may have been influenced by the lower ages seen in the phrenic nerve group. In another retrospective case control study, Esclarin et al. (1994) reports higher rates of power wheelchair management, phonation success, patient satisfaction and hospital discharge in paced subjects compared to mechanically ventilated subjects. A basic cost analysis in that study suggested increased costs of 50 hours per year for ventilatory management in the mechanically ventilated group (Esclarin et al. 1994). However, the small numbers, the difficulty in comparing baseline statistics in the two groups, the potential for selection bias in the subjects receiving pacemakers and the overall high rate of death in the high lesion spinal cord injury population make this data very difficult to interpret. Prospective comparison studies looking at morbidity, mortality, quality of life and costs related to phrenic and diaphragmatic pacing are lacking.

Several different devices for phrenic nerve pacing have been developed. Many of the reported studies are level 4 case series or pre-post study designs looking at the feasibility of phrenic nerve stimulation devices. Reported benefits to subjects include improved sense of smell, mobility, quality of speech and overall sense of well-being (DiMarco et al. 2005b). Long-term partial or total independence from mechanical ventilation can generally be interpreted as a successful intervention with these devices.

There are several small level 4 studies to show that bilateral phrenic nerve pacing and bilateral diaphragmatic pacing can be used successfully for the ventilation of subjects with SCI (Kaufman et al. 2015; Posluszny et al 2013; Baer et al. 1990; DiMarco et al. 2005a; Elefteriades et al. 2002; Glenn et al. 1976; Sharkey et al. 1989; Mayr et al. 1993; Oakes et al. 1980; Miller et al. 1990; Nakajima and Sharkey 1990; Onders et al. 2004). More recent studies have included large sample sizes including the study by Alshekhlee et al. (2008) (n = 26).

For subjects without intact bilateral phrenic nerves, there is one small level 4 study to show that unilateral phrenic pacing in combination with intercostals stimulation can be used successfully for the ventilation of subjects with SCI with only one intact phrenic nerve (DiMarco et al. 2005b). In addition, there is one small level 4 study reporting on successful phrenic nerve stimulation following intercostal nerve to phrenic nerve transfer in a case series of 6 subjects with C3-C5 injuries (Krieger and Krieger 2000). There is level 4 evidence to show that intercostal muscle pacing via upper thoracic ventral root stimulation alone has not succeeded in supporting ventilation for prolonged periods (DiMarco et al. 1994).

There are high complication rates reported with these devices. Many of these are likely due to the learning curve involved in successful subject selection, surgical technique development and the “prototype” or single unit design of the devices themselves with a higher inherent risk of technical failure (Baer et al. 1990). There is at least one case report of the successful off label use of a spinal cord stimulator (rather than a purpose built phrenic nerve stimulator) being used to stimulate the phrenic nerves in subjects with SCI (Taira and Hori 2007).

Potential complications of phrenic pacing include wires breaking, wires or receivers becoming displaced, devices failing, aspiration of food during inspiration, shoulder or abdominal pain and infections (Baer et al. 1990; DiMarco et al. 2005a, 2005b). With the laparoscopic approach for diaphragm pacing, subjects may develop pneumothoraces or subcutaneous emphysema (DiMarco et al. 2005a).

Conclusion

There is level 3 evidence (from 1 case control study: Carter 1993) that suggests a higher survival rate in a phrenic nerve paced group compared to a mechanically ventilated group.

There is level 3 evidence (from 1 case control study: Esclarin et al. 1994) that suggests better power wheelchair management, phonation success, patient satisfaction and hospital discharge in phrenic paced subjects compared to mechanically ventilated subjects.

There is level 4 evidence (from 10 pre-post studies: see Table 19) that phrenic nerve stimulation can be used as a long-term alternative to mechanical ventilation for subjects with injuries at C2 or above.

There is level 4 evidence from (1 pre-post study: Alshekhlee et al. 2008) that diaphragm pacing system (DPS) can help cervical SCI patients breathe without a mechanical ventilator.

There is level 4 evidence (Tedde et al. 2012; DiMarco et al. 2005a; Onders et al. 2004) that diaphragmatic stimulation via laparoscopic placement of electrodes can be used as a long-term alternative to mechanical ventilation for subjects with high cervical spinal cord injuries.

There is level 4 evidence from 1 study (DiMarco el al. 2005b) that unilateral phrenic stimulation in combination with intercostals stimulation can be used as an alternative to mechanical ventilation for subjects with a single intact phrenic nerve. There is level 4 evidence from 1 study (DiMarco et al. 1994) to show that intercostal muscle pacing via upper thoracic ventral root stimulation cannot be used as a long-term alternative to mechanical ventilation (DiMarco et al. 1994).

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